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Hum Mutat. 2016 Mar;37(3):242-5. doi: 10.1002/humu.22933. Epub 2015 Dec 15.

Identification and Characterization of a Novel Constitutional PIK3CA Mutation in a Child Lacking the Typical Segmental Overgrowth of "PIK3CA-Related Overgrowth Spectrum".

Author information

1
Institute for Clinical Genetics, Faculty of Medicine Carl Gustav Carus, TU Dresden, Germany.
2
Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, Washington.
3
Division of Genetic Medicine, Department of Pediatrics, University of Washington, Seattle, Washington.
4
Genome Damage & Stability Centre, School of Life Sciences, University of Sussex, Falmer, Brighton, UK.

Abstract

Activating somatic PIK3CA mutations underlie a growing heterogeneous spectrum of segmental overgrowth disorders. We report the identification and evaluation of a novel de novo constitutional PIK3CA mutation (NM_006218.2:c.335T>A, p.Ile112Asn) in a child with congenital megalencephaly and macrosomia. Functional characterization of patient cells using a variety of endpoints demonstrates increased phosphatidylinositol-3-kinase (PI3K) activity. The mutation lies in a linker region adjacent to the p85 (PIK3R2) binding domain of the p110α (PIK3CA) catalytic subunit of PI3K. We show that altered stoichiometry within the p85-p110 complex likely underlies the hyperactive PI3K-AKT-mTOR signaling in this instance. Our findings expand upon the recently proposed "PIK3CA-related overgrowth spectrum" associated with PIKC3A mutations and PI3K hyperactivation, adding constitutional PIK3CA mutations as an underlying cause of megalencephaly and macrosomia in newborns.

KEYWORDS:

PIK3CA; macrocephaly; overgrowth; p110α

PMID:
26593112
PMCID:
PMC4752430
[Available on 2017-03-01]
DOI:
10.1002/humu.22933
[Indexed for MEDLINE]
Free PMC Article

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